Basic enol ether and acid addition salts thereof

ABSTRACT

The present invention is related to new basic enol ethers having the general formula ##STR1## and to the pharmacologically acceptable acid addition salts thereof. The invention is further related to process for the treatment of spasmodic conditions in humans by administering a compound of the above general formula or a pharmacologically acceptable acid addition salt thereof to a human suffering from such conditions.

This invention relates to new basic enol ethers and to theirpharmacologically acceptable acid addition salt. The invention furtherrelates to pharmaceutical compositions containing the new compounds asactive principle.

The compounds according to the invention correspond to the followinggeneral formula: ##STR2## wherein R₁ represents a member selected fromthe group consisting of the unsubstituted phenyl, pyridyl and thienylgroup and such groups (preferably the phenyl group) substituted bymembers selected from the group consisting of halogen (preferablybromine, chlorine and fluorine, most preferably chlorine), lower alkylhaving from 1 to 4 carbon atoms, nitro,

Trifluoromethyl, hydroxy and lower alkoxy having from 1 to 4 carbonatoms, alk represents a member selected from the group consisting of thelinear and branched alkylene groups having from

2 to 4 carbon atoms, and

R₂ and R₃, which may be the same or different, represent membersselected from the group consisting of hydrogen, alkyl having from 1 to 4carbon atoms and,

R₂ and R₃ together, an alpha, omega-polymethylene group containing from4 to 5 methylene groups and the polymethylene group containing 4methylene groups and an oxygen in the chain symmetrically positionedtherein.

Of the compounds corresponding to general formula I, those are preferredwherein R₁ represents a member selected from the group consisting of theunsubstituted phenyl group and the phenyl group monosubstituted in theortho position as already indicated, alk has the same meaning as aboveindicated and most preferably represents the ethylene group, and R₂ andR₃ which may be the same or different, represent a member selected fromthe group consisting of hydrogen and the alkyl groups having from 1 to 4carbon atoms, most preferably both R₂ and R₃ representing the ethylgroup.

Suitable acid addition salts are, in particular, those of hydrochloricacid, sulphuric acid, phosphoric acid, acetic acid, glycolic acid,lactic acid, maleic acid, succinic acid, tartaric acid, citric acid,benzoic acid, malic acid, β-hydroxy naphthoic acid and embonic acid.

The compounds of general formula I may be prepared by one of thefollowing methods:

A. a compound corresponding to the general formula ##STR3## in which R₁has the same meaning as in formula I and either

R₄ and R₅ together represent a bond and

R₆ represents Me, or

R₄ represents as separable group such as --C.tbd.CH, --CH₂ SOCH₃, --CNor --CH₂ NO₂, and

R₅ and R₆ represent hydrogen atoms, is reacted with a compoundcorresponding to the general formula ##STR4## in which Y is a halogenatom or a sulphonic acid ester group, and alk, R₂ and R₃ have the samemeaning as in formula I, at room temperature or at elevated temperaturein a suitable solvent and in the presence of a basic condensation agent,

Me in formula II being the cation of the basic condensation agent used,or

B. a compound corresponding to the general formula ##STR5## in which Xis a chlorine or bromine atom and

R₁ and alk have the same meaning as in formula I, is reacted with acompound corresponding to the general formula ##STR6## in which R₂ andR₃ have the same meaning as in formula I, in the presence of anacid-binding agent at room temperature or elevated temperature and undernormal or elevated pressure in a suitable solvent, or

C. a compound corresponding to the general formula ##STR7## in which R₁,R₂ and R₃ have the same meaning as in formula I, and Z is a linear orbranched alkylene group with 1 to 3 carbon atoms, is reacted with acomplex metal hydride, preferably with lithium aluminium hydride, in asuitable inert solvent either at room temperature or at elevatedtemperature, or

D. a compound corresponding to the general formula ##STR8## in which R₇is a lower alkyl group with 1 to 4 carbon atoms and

R₈ and R₉ together represent a bond or

R₉ is a hydrogen atom and

R₈ is a lower alkoxy group with 1 to 4 carbon atoms and

R₁ has the same meaning as in formula I, is reacted with a compoundcorresponding to the general formula ##STR9## in which alk, R₂ and R₃have the same meaning as in formula I, in the presence of an acidcatalyst at room temperature or elevated temperature and in the presenceor absence of an organic solvent.

The basic condensation agent used in the methods described above is, forexample, sodium hydride, sodium amide, sodium oxide, sodium or potassiumhydroxide or alcoholate or potassium tert.-butylate.

Suitable acid-binding agents are tertiary aliphatic and aromatic organicamines and N-containing heterocycles, although it is preferred to use anexcess of the amines of general formula V used for the reaction itself.

Preferred acid catalysts are hydrochloric acid, sulphuric acid,phosphoric acid and p-toluene sulphonic acid. Suitable organic solventsare benzene, toluene and xylene, dioxan, tetrahydrofuran and diethylether, alcohols such as methanol, ethanol and isopropanol, alsochlorinated organic solvents such as methylene chloride, chloroform,1,2-dichloroethane and chlorobenzene, as well as dipolar aproticsolvents such as dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone and dimethyl sulphoxide or mixtures thereof.

Preferred solvents for method A) are benzene, toluene, xylene and thedipolar aprotic solvents, preferred solvents for method B), in additionto those mentioned in reference to method A), are alcohols such asmethanol, ethanol and isopropanol, preferred solvents for method C) arediethyl ether, tetrahydrofuran and dioxan, and preferred solvents formethod D) are chlorinated organic solvents such as methylene chloride,chloroform, 1,2-dichloroethane and chlorobenzene.

The methods according to the invention are carried out at temperaturesin the range from 0° to 150° C under normal pressure or elevatedpressure. However, method B) is preferably carried out at temperaturesbetween 40° and 140° C under elevated pressure, optionally in anautoclave, whereas the other methods are preferably carried out undernormal pressure at temperatures between 15° C and the boilingtemperature of the solvent.

The basic enol ethers of general formula I prepared by the methodsdescribed above are cis-trans isomers which may optionally be separated.

The compounds according to the invention may be converted into theiracid addition salts by the usual methods, or the free bases or othersalts may be prepared from the acid addition salts obtained by the usualmethods.

The compounds of general formula I and their acid addition salts havevaluable pharmacological properties. Above all, they are effectivespasmolytics, although they also show anti-allergic, anti-depressive andtremor-inhibiting activity. Their spasmolytic acitivity was tested insitu by the method reported by N. BROCK, D. LORENZ and H. BARTLING inArch. Ex. Path. Pharmacol. 215, 512 - 524 (1952) where the activecompound is injected intravenously into the small intestine of guineapigs. The DE 75 is the dose which reduces by 75% the spasms caused byneostigmine or barium chloride. For example, the substances of Examples3 and 18 are considerably more effective than the standard substancesCamylofin and papaverine. The myotropic spasmolytic activity ofCamylofin (BaCl₂ -induced spasm) is exceeded by the factor seven by thecompound of Example 3 and by the factor eleven by the compound ofExample 18. The neurotropic spasmolytic activity of Camylofin(neostigmine-induced spasm) is exceeded by the factor two by thecompound of Example 3 and by the factor six by the compound of Example18. In the model test, papaverine is only active in higher subtoxicdoses (serious breathing difficulties).

The pharmacological properties are set out in Table 1 below:

                                      Table 1                                     __________________________________________________________________________    Spasmolytic activity                                                                 neostigmine spasm    BaCl.sub.2 - spasm                                                 relative activity based                                                                            relative activity based                        DE 75     on Camylofin = 1.0                                                                       DE 75     on Camylofin = 1.0                      Preparation                                                                          mg/kg.                                                                             μmol/kg.                                                                        mg/kg.                                                                             μmol/kg.                                                                         mg/kg.                                                                             μmol/kg.                                                                        mg/kg.                                                                             μmol/kg.                        __________________________________________________________________________    Compound of                                                                   Example 3                                                                            2.11 7.09 1.94 1.47  1.04 3.49 7.02 5.33                               Compound of                                                                   Example 18                                                                           0.683                                                                              2.19 6.00 4.75  0.685                                                                              2.20 10.66                                                                              8.45                               papaverine                                                                           18.9 55.8 0.22 0.186 26.0 69.0 0.28 0.27                               Camylofin                                                                            4.1  10.4 1.00 1.00  7.3  18.6 1.00 1.00                               __________________________________________________________________________

On the basis of the degree to which the spontaneous colon peristalsis ofnon-anaesthetized dogs is suppressed, the compound of Example 3administered intravenously is 8.4 times more active than Camylofin. Anenteral activity of 9.2% can be calculated from the quotient of theactive doses after intravenous and enteral administration. In additionto the significant increase in spasmolytic activity, there is anappreciable reduction in systemic side effects based on the neurotropicactivity component. Neither the intravenous application nor the enteralapplication of spasmolytically active doses produced the least sign ofmydriasis in non-anaesthetized dogs. A moderate increase in heart rateafter intravenous administration, of which the trend corresponds to thespasmolytic effect in the case of Camylofin and also in the case of allother commercial spasmolytics, disappears again after only 2 minutes inthe case of the compound of Example 3 and is in no way related toblocking of the colon peristalsis which lasts for more than 30 minutes.Accordingly, this compound achieves a hitherto unknown organ specificityin its spasmolytic effect. Hence this compound is particularlypreferred.

The toxic doses of the compound of Example 3 are somewhat higher thanthose of Camylofin in rats, mice and dogs, irrespective of the method ofadministration. The approximately 10% reduction in toxicity and the morethan 8-fold increase in activity give this compound a therapeutic indexwhich is greater by about the factor ten than that of the standardsubstance Camylofin.

In the case of the compound of Example 18, the toxic doses are somewhatlower than in the case of Camylofin. However, in view of the significantincrease in spasmolytic activity on the ileum of guinea pigs, itstherapeutic index is once again greater by about the factor seven.

Table 2

Acute toxicity in mice (DL 50 [mg/kg]) with intravenous administration

    ______________________________________                                        Compound of     DL 50                                                         Example No.     [mg./kg.]                                                     ______________________________________                                         3              40.7                                                          18              30.3                                                          Camylofin       36.2                                                          ______________________________________                                    

The compounds of the present invention are most useful in the treatmentof spasmodic conditions in humans, in particular such conditions of theabdominal viscera such as colics of the biliary and urinary tracts,tenesmic attacks of the bladder, ulcer pain, dysmenorrheas or for theeasing of labors. The compounds are administered orally orintraperitoneally in usual forms such as dragees, tablets, suppositoriesor injection solutions in daily doses ranging from 5 to 60 mg, of thebase compound or the equivalent amount of a suitable acid addition saltthereof, with 5 to 10 mg. of the base or the equivalent amount of a saltas single dose. For instance 1 to 2 tablets containing 10 mg. of thebase or the equivalent amount of a salt are administered 2 to 3 times aday or 1 to 2 ml. of an injection solution containing 10 mg./2 ml. ofthe base or the equivalent amount of a salt are slowly injectedintravenously or intramuscularly.

The invention is illustrated by the following Examples without howeverlimiting the same thereto.

EXAMPLE 1N,N-Dimethyl-N-{2-[α-(tricyclo(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A suspension of 3.9 g. (0.1 mol) of sodium amide in 45 ml of anhydroustoluene was heated to boiling point, followed by the dropwise additionwith stirring of a solution of 19.83 g. (0.1 mol) oftricyclo-(2.2.1.0².6)hept-3-yl phenyl ketone and 10.76 g. (0.1 mol) ofβ-dimethy amino ethyl chloride in 85 ml. of anhydrous toluene. Afterstirring at reflux temperature for 1.5 hours, the mixture was cooled toroom temperature and 30 ml. of water added to destroy the sodium amide.The organic phase was then separated off, washed three times with 30 ml.of water, dried over anhydrous sodium sulphate and concentrated invacuo. The crude base left was dissolved while cooling with ice in amixture of 9.85 g. (0.1 mol) of 37% hydrochloric acid in 60 ml. ofwater, after which the aqueous solution was extracted three times with30 ml. of ether, the aqueous phase separated off and a solution of 10ml. of 10N sodium hydroxide in 20 ml. of ice water added dropwise to itwhile cooling. The mixture was extracted with a total of 150 ml. ofether, the ether phase was dried over anhydrous sodium sulphate, theinorganic salt filtered off and the product concentrated in vacuo. Thecrude base obtained was purified through an aluminium oxide column,followed by fractionation in a high vacuum.

BP₀.002 : 107° - 115° C. Yield: 20.5 g. (76% of the theoretical)Hydrochloride: Mp: 168° - 171° C. (from ethyl acetate/isopropanol

EXAMPLE 2N-Ethyl-N-{2-[α-(tricyclo(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 90 g. (0.345 mol) ofβ-chloroethyl-{α-[tricyclo-(2.2.1.0².6)hept-3-ylidene]-benzyl}-ether and69 g. (1.53 mol) of ethylamine in 250 ml. of anhydrous benzene washeated for 5 hours to 140° C. in a 1 liter capacity autoclave. Aftercooling, the ethylamine hydrochloride was filtered off under suction,the mother liquor concentrated in vacuo and the residue subjected toacid-alkaline working up. The basic fraction was fractionated in vacuo.

Bp 0.08: 130° 14 134° C. Hydrochloride: Mp. 185° - 186° C.

EXAMPLE 3N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A suspension of 46.8 g. (1.2 mol) of sodium amide in 450 ml. ofanhydrous toluene was heated to boiling point, followed by the dropwiseaddition with stirring of a solution of 198.3 g. (1 mol) oftricyclo-(2.2.1.0².6)hept-3-yl phenyl ketone and 162.7 g. (1.2 mol) ofβ-diethyl amino ethyl chloride in 850 ml. of anhydrous toluene. Afterstirring at reflux temperature for 1 hour, the reaction mixture wascooled to room temperature and 300 ml. of water added dropwise todestroy the sodium amide. The organic phase was then separated off,washed three times with 300 ml. of water, dried over anhydrous sodiumsulphate and concentrated in vacuo. The crude base left was dissolvedwhile cooling with ice in a mixture of 110 g. of 37% hydrochloric acidand 900 ml. of water, after which the aqueous solution was extractedtwice with 400 ml. of ether, the aqueous phase separated off andextracted three times with 800 ml. of chloroform. The combinedchloroform extracts were washed with 800 ml. of water and dried overanhydrous sodium sulphate. After filtration, the chloroform solution wasconcentrated by evaporation in vacuo. The residue was dissolved in 500ml. of water, a solution of 60 g. of sodium hydroxide in 100 ml. ofwater added while cooling with ice and the mixture extracted with atotal of 1 liter of peroxide-free ether. The ether phase was dried withanhydrous sodium sulphate, concentrated by evaporation in vacuo and theresidue left fractionated.

Bp 0.1: 140° - 145° C. Yield: 243 g. (81.7% of the theorezical).Hydrochloride: To prepare the hydrochloride, the base was dissolved inanhydrous ether, and somewhat less than the theoretical quantity ofanhydrous HCl-containing ether added with vigorous stirring and coolingwith ice. The hydrochloride precipitated was filtered off under suction,washed with anhydrous ether and recrystallized from ethyl acetate.

Mp: 127° C.

Hydrogen fumarate: To prepare the hydrogen fumarate, the base wasdissolved in isopropanol and the theoretical quantity of fumaric acid ina little isopropanol added with vigorous stirring and cooling with ice.The salt which crystallized after only a short time was filtered offunder suction and purified with anhydrous ether.

Mp: 123° - 126° C. (from isopropanol).

EXAMPLE 4N,N-Diethyl-N-{-2-[α-tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 99.2 g. (0.5 mol) of tricyclo-(2.2.1.0².6) hept-3-ylphenyl ketone in 150 ml. of anhydrous toluene was added to a suspensionof 18 g. (0.6 mol) of sodium hydride (80% in mineral oil) in 200 ml. ofanhydrous toluene. After heating for 1 hour to 70° C., the reactionmixture was cooled to room temperature, followed by the dropwiseaddition of a solution of 81.3 g. (0.6 mol) of β-diethyl amino ethylchloride in 100 ml. of anhydrous toluene, and then by heating for 2hours to boiling point. After the reaction solution had cooled, waterwas added to it, followed by working up in the same way as in Example 3.The compound in question was isolated in the form of its hydrochloride.

Hydrochloride: 123° - 125° C. (from ethyl acetate).

EXAMPLE 5N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

18 g. (0.6 mol) of sodium hydride (80% in mineral oil) and 250 ml. ofdimethyl sulphoxide were heated with stirring for 1.5 hours at 70° C.until the evolution of hydrogen was over. After cooling to roomtemperature, a solution of 99.2 g. (0.5 mol) oftricyclo-(2.2.1.0².6)hept-3-yl phenyl ketone in 150 ml. of dimethylsulphoxide was added and stirring continued for another hour duringwhich the temperature rose to 50° - 55° C. A solution of 81.3 g. (0.6mol) of β-diethyl amino ethyl chloride in 100 ml. of dimethyl sulphoxidewas then added dropwise, followed by heating for another hour to 75° C.after the exothermic reaction had abated and the reaction temperaturerisen to 70° C. After cooling to room temperature, the reaction mixturewas diluted with water, the aqueous solution was extracted with ether,the ethereal phase was dried with anhydrous sodium sulphate, filteredand concentrated in vacuo. The residue was dissolved in a mixture of 55g. of concentrated hydrochloric acid and 450 g. of ice water, purifiedtwice with 200 ml. of ether and, finally, the aqueous solution extracted3 times with 400 ml. of chloroform. The combined chloroform extractswere purified with 400 ml. of water, dried over anhydrous sodiumsulphate and concentrated in vacuo. The residue was alkalized, purifiedand fractionated in aqueous solution in the same way as in Example 3.

Bp. 0.1: 140° - 145° C. Yield: 129.4 g. (87% of the theoretical).Hydrochloride: 123° - 126° C. (from ethyl acetate).

EXAMPLE 6N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

5.48 g. (0.114 mol) of a 50% sodium hydride/mineral oil dispersion wererepeatedly washed with petroleum ether in a nitrogen atmosphere,decanted off from the solvent, dried in vacuo and 80 ml. of anhydrousdimethyl formamide added dropwise under nitrogen while stirring andcooling with ice. This was followed by stirring for 30 minutes at 0° C.A solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.0².6)hept-3-ylphenyl ketone in 30 ml. of anhydrous dimethyl formamide was then addeddropwise, the mixture stirred for 15 minutes and, finally, a solution of15.1 g. (0.111 mol) of β-diethyl amino ethyl chloride in 40 ml. ofanhydrous dimethyl formamide added to it. The reaction mixture was thenstirred for 30 minutes at 0° C., for 15 hours at room temperature andthen for 3 hours at 40° C., the solvent evaporated off in a high vacuumand 44 ml. of 2N HCl added to the residue while cooling with ice/commonsalt. The reaction solution was purified with a total of 150 ml. ofether, extracted three times with 70 ml. of chloroform, the combinedchloroform extracts dried with anhydrous sodium sulphate andconcentrated in vacuo. The basic enol ether accumulating in the form ofits hydrochloride was crystallized with ether. Hydrochloride: Mp: 120° -123° C. (from ethyl acetate).

EXAMPLE 7N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl-}amine

5.48 g. (0.114 mol) of a 50% sodium hydride/mineral oil dispersion werepurified as described in Example 6, followed by the addition undernitrogen while stirring and cooling with ice/common salt of 80 ml. ofanhydrous N-methyl pyrrolidone and a solution of 19.83 g. (0.1 mol) oftricyclo-(2.2.1.0².6) hept-3-yl phenyl ketone in 25 ml. of anhydrousN-methyl pyrrolidone, and then by the dropwise addition of 15.1 g.(0.111 mol) of β-diethyl amino ethyl chloride in solution in 20 ml. ofanhydrous N-methyl pyrrolidone. After stirring for 15 hours at roomtemperature and then for 7 hours at 45° C., the reaction solution wasdiluted with 600 ml. of water and the aqueous solution extracted withether. The ether extracts were dried over anhydrous sodium sulphate,filtered and concentrated in vacuo. The theoretical quantity of 2Nhydrochloric acid was then added to the residue of the crude base whilecooling with ice, and the required hydrochloride isolated in the sameway as described in Example 6.

Hydrochloride: Mp: 123° - 125° C. (from ethyl acetate). Yield: 25.8 g.(77.2% of the theoretical).

EXAMPLE 8N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A mixture of 15.71 g. (0.14 mol) of potassium tert.-butylate in 80 ml.of anhydrous dimethyl sulphoxide was heated for 1 hour to 70° C., cooledto room temperature and a solution of 19.83 g. (0.1 mol) oftricyclo-(2.2.1.0².6)hept-3-yl phenyl ketone in 25 ml. of anhydrousdimethyl sulphoxide added with stirring in a nitrogen atmosphere. Afterstirring for 1 hour at 40° C., a solution of 18.98 g. (0.14 mol) ofβ-diethyl amino ethyl chloride in 15 ml. of anhydrous dimethylsulphoxide was added dropwise with continued stirring, the mixturestirred for another 15 minutes at room temperature and then for 4 hoursat 55° C. and finally worked up in the same way as described in Example5.

Bp. 0.1: 135° - 140° C. Hydrochloride: Mp. 121° - 124° C. (from ethylacetate).

EXAMPLE 9N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 14 g. (53.6 mMol) ofβ-chloroethyl-{α-[tricyclo-(2.2.1.0².6)hept-3-ylidene]-benzyl}-ether and20 g. (0.273 mol) of diethyl amine in 130 ml. of benzene was heated for5 hours to 140° C. in a 0.5 liter autoclave. After cooling, the diethylamine hydrochloride was filtered off under suction, benzene and diethylamine distilled off in vacuo and the residue left subjected toacid-alkaline working up. The basic fraction was fractionated in vacuo.

Bp. 0.1: 140° - 145° C. Hydrochloride: Mp: 123° - 125° C. (from ethylacetate).

EXAMPLE 10N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 39 g. (0.125 mol) ofα-[tricyclo-(2.2.1.0².6)hept-3-ylidene]-benzyloxy aceticacid-N,N-diethyl amide in 300 ml. of anhydrous ether was added dropwiseto a suspension of 7.1 g. (0.187 mol) of lithium aluminium hydride in100 ml. of anhydrous ether. On completion of the reaction, the reactionproduct was decomposed with water, followed by filtration under suction.The ethereal phase was concentrated by evaporation in vacuo. The oilyresidue left was fractionated in a high vacuum.

Bp: 0.05: 132° - 136° C. Yield: 30 g. (80.6% of the theoretical).Hydrochloride: Mp.: 121° - 123° C. (from ethyl acetate).

EXAMPLE 11N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 7.9 g. (34.9 mMol) ofethyl-{α-[tricyclo-2.2.1.0².6)-hept-3-ylidene]-benzyl}-ether and 21.4 g.(0.182 mol) of β-diethyl amino ethanol in 35 ml. of anhydrous chloroformwas adjusted to pH 3.5° - 4 with concentrated hydrochloride acid. Afterstirring for 5 days at room temperature, another 3 drops of concentratedhydrochloric acid were added, the reaction mixture concentrated after 24hours at room temperature, the residue taken up in water, extracted withpetroleum ether and finally with chloroform. The chloroform phase waswashed with a little water, dried with anhydrous sodium sulphate,filtered, concentrated in vacuo and crystallized with petroleum ether.

Hydrochloride: Mp.: 118° - 120° C.

N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-p-hydroxybenzyloxy]-ethyl}-amine was prepared by the same method andcharacterized by thin layer chromatography through the Rf-value 0.796 onsilica gel in the eluent benzene : ethanol : concentrated ammonia (65 :30 : 5).

EXAMPLE 12N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A solution of 4.5 g. (18.4 mMol) of tricyclo-(2.2.1.0².6)-hept-3-ylphenyl ketone dimethyl acetal in 7 ml. of methylene chloride and 4 dropsof ethereal hydrochloric acid (100 mg. of HCl/ml.) in 1 ml. of methylenechloride were added dropwise with stirring over a period of 5 minutes at55° C. to a solution of 2.83 g. (18.4 mMol) of β-diethyl amino ethanolhydrochloride in 35 ml. of anhydrous methylene chloride. The reactionmixture is immediately concentrated in vacuo, evaporated three timeswith 1 ml. of water, taken up in a little water, the aqueous phasepurified with ether and extracted with chloroform. The chloroformsolution was concentrated and the residue crystallized with ether.

Hydrochloride: Mp.: 116° - 120° C.

EXAMPLE 13N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amine

A suspension of 19.5 g. (0.5 mol) of sodium amide in 250 ml. ofanhydrous toluene was heated to boiling point, followed by the dropwiseaddition with stirring of a solution of 112.15 g. (0.5 mol) ofα-ethinyl-α-[tricyclo-(2.2.1.0².6)hept-3-yl]-benzyl alcohol and 67.7 g.(0.5 mol) of β-diethyl amino ethyl chloride in 450 ml. of anhydroustoluene. After stirring for 1 hour at reflux temperature, the reactionmixture was cooled to room temperature and 125 ml. of water addeddropwise. The organic phase was then separated off, washed three timeswith 125 ml of water, dried over anhydrous sodium sulphate andconcentrated in vacuo. The crude base left was purified in the

same way as in Example 3.

Bp. 0.1: 140°-145° C. Yield: 124 g. (83.3% of the theoretical).Hydrochloride: 121°-123° C. (from ethyl acetate).

EXAMPLE 14N-{2-[α-(Tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-morpholine

A solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.0².6)-hept-3-ylphenyl ketone in 45 ml. of anhydrous toluene was added while stirringand boiling to a suspension of 3.9 g. (0.1 mol) of sodium amide in 45ml. of anhydrous toluene, followed by etherification with a solution of14.96 g. (0.1 mol) of N-(2-chloroethyl)-morpholine in 45 ml. ofanhydrous toluene in the same way as in Example 3.

Bp: 0.001: 160°-170° C. Yield: 26.2 g. (84.3% of the theoretical).Hydrochloride: 170°-173° C. (from ethyl acetate/isopropanol).

EXAMPLE 15N-Methyl-2-{2[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-pyrrolidine

5.28 g. (0.11 mol) of a 50% sodium hydride/mineral oil dispersion werepurified as in Example 6, followed by the dropwise addition whilestirring under nitrogen of 80 ml. of dimethyl sulphoxide. The reactionmixture was then heated for 30 minutes at 70°-80° C. until the evolutionof hydrogen stopped, after which it was cooled to room temperature and asolution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.0².6)-hept-3-yl phenylketone in 25 ml. of dimethyl sulphoxide added dropwise to it. Afterstirring for another hour at 35°-40° C., 16.25 g. (0.11 mol) of N-methylpyrrolidyl-2-ethyl chloride in 15 ml. of dimethyl sulphoxide were addedand the mixture stirred for another 2.5 hours at 35° to 40° C. Thereaction mixture was then poured into 300 ml. of water, the oilprecipitated was extracted with ether and the ether phase dried withanhydrous sodium sulphate. Filtration and concentration of the solventby evaporation in vacuo left an oily residue which was converted intothe hydrochloride in chloroform with 2N hydrochloric acid.

Hydrochloride: Mp.: 183°-186° C. (from ethyl acetate/isopropanol).

Yield: 25.3 g. (73.1 % of the theoretical).

EXAMPLE 16N,N-Dimethyl-N-{3-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-propyl}-amine

A solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.0².6)-hept-3-ylphenyl ketone in 45 ml. of anhydrous toluene was added while stirringand boiling to a suspension of 3.9 g. (0.1 mol) of sodium amide in 45ml. of anhydrous toluene, followed by etherification as in Example 3with a solution of 12.2 g. (0.1 mol) of γ-dimethyl amino propyl chloridein 50 ml of anhydrous toluene.

Bp. 0.005: 135°-142° C. Yield: 22.3 g. (79% of the theoretical).Hydrochloride: 145°-148° C. (from ethyl acetate/isopropanol).

EXAMPLE 17N,N-Diethyl-N-{3-[α-(tricyclo-(2.2.1.0.².6)hept-3-ylidene)-benzyloxy]-propyl}-amine

A mixture of 90 g. (0.327 mol) ofγ-chloropropyl-{α-[tricyclo-(2.2.1.0².6)hept-3-ylidene]-benzyl}-ether,96 g. (1.31 mol) of diethyl amine and 250 ml. of benzene, was heated for4 hours to 160° C. in a 1 liter autoclave. After cooling, the diethylamine hydrochloride was filtered off under suction, benzene and diethylamine distilled off in vacuo and the residue left subject toacid-alkaline working up. The basic fraction was dried in ethereal phaseover anhydrous sodium sulphate, filtered, concentrated and fractionatedin vacuo.

Bp. 0.01: 135°-140° C. Yield: 72 g. (70.7% of the theoretical).Hydrochloride: Mp.: 104°-110° C. (from ethyl acetate).

EXAMPLE 18N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-o-methylbenzyloxy]-ethyl}-amine

A suspension of 16.77 g. (0.43 mol) of sodium amide in 195 ml. ofanhydrous toluene was heated to boiling point, followed by the dropwiseaddition with stirring of a solution, of 91.3 g. (0.43 mol) oftricyclo-(2.2.1.0².6)hept-3-yl-o-tolyl ketone and 58.3 g. (0.43 mol) ofβ-diethyl amino ethyl chloride in 370 ml. of anhydrous toluene. Afterstirring for 3.5 hours at reflux temperature, the mixture was cooled toroom temperature and 130 ml. of water added to destroy the sodium amide.The organic phase was separated off and purified, subjected toacid-alkaline working up and fractionated in a high vacuum in the sameway as in Example 3.

Bp. 0.04: 136°-144° C. Yield: 95.1 g. (71% of the theoretical).Hydrochloride: 153°-155° C. (from ethyl acetate).

EXAMPLE 19N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-p-methylbenzyloxy]-ethyl}-amine

A solution of 21.23 g. (0.1 mol) oftricyclo-(2.2.1.0².6)-hept-3-yl-p-tolyl ketone in 45 ml. of anhydroustoluene was added while stirring and boiling to a suspension of 3.9 g.(0.1 mol) of sodium amide in 45 ml. of anhydrous toluene followed byetherification as in Example 3 with a solution of 13.56 g. (0.1 mol) ofβ-diethyl amino ethyl chloride in 45 ml.of anhydrous toluene.

Bp. 0.002: 129°-136° C. Hydrohloride: 146°-148° C. (from ethyl acetate).

EXAMPLE 20N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-m-chlorobenzyloxy]-ethyl}-amine

A solution of 23.3 g. (0.1 mol) oftricyclo-(2.2.1.0².6)-hept-3-yl-m-chlorophenyl ketone in 45 ml. ofanhydrous toluene was added while stirring and boiling to a suspensionof 3.9 g. (0.1 mol) of sodium amide in 45 ml. of anhydrous toluene,followed by etherification as in Example 3 with 13.56 g. (0.1 mol) ofβ-diethylamino ethyl chloride in 45 ml. of anhydrous toluene. Thereaction product was worked up in the same way as in Example 3, thecrude base obtained was purified through an aluminium oxide column andfractionated.

Bp. 0.07: 158°-164° C. Yield: 23.6 g. (71.1% of the theoretical).Hydrochloride: 110°-114° C. (from benzene/petroleum ether).

EXAMPLE 21N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-p-chlorobenzyloxy]-ethyl}-amine

A solution of 23.3 g. (0.1 mol) oftricyclo-(2.2.1.0².6)-hept-3-yl-p-chlorophenyl ketone in 45 ml. ofanhydrous toluene was added while stirring and boiling to a suspensionof 3.9 g. (0.1 mol) of sodium amide in 45 ml. of anhydrous toluene,followed by etherification as in Example 3 with a solution of 13.56 g.(0.1 mol) of β-diethyl amino ethyl chloride in 45 ml. of anhydroustoluene.

Bp. 0.01: 150°-157° C. Yield: 24.2 g. (73% of the theoretical).

Hydrochloride: 112°-114° C. (from ethyl acetate).

EXAMPLE 22N,N-Diethyl-N-{2-[1-(2-pyridyl)-1-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-methoxy]-ethyl}-amine

2.57 g. (53.6 mMol) of a 50% sodium hydride/mineral oil dispersion werepurified in the same way as in Example 6, followed by the dropwiseaddition while stirring under nitrogen of 40 ml. of dimethyl sulphoxide.The reaction mixture was then heated for 30 minutes at 70° to 80° C.until the evolution of hydrogen was over, cooled to room temperature, asolution of 9.7 g. (48.7 mMol) oftricyclo-(2.2.1.0².6)hept-3-yl-(2-pyridyl)-ketone in 10 ml. of dimethylsulphoxide added dropwise, the mixture stirred for another at 35 to 40°C., 7.27 g. (53.6 mMol) of β-diethyl amino ethyl chloride in 10 ml. ofdimethyl sulphoxide added and the mixture stirred for another hour at 35to 40° C. The reaction mixture was then diluted with 300 ml. of water,extracted with ether and the ether phase dried with anhydrous sodiumsulphate. Filtration and concentration of the ethereal solution byevaporation in vacuo left an oily residue which was purified through analuminum oxide column and converted into the monohydrochloride of therequired compound in the usual way with ethereal hydrochloric acid.

Monohydrochloride: Mp.: 132°-135° C.

EXAMPLE 23N,N-Diethyl-N-{2-[1-(4-pyridyl)-1-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-methoxy]-ethyl}-amine

A solution of 17.87 g. (89.6 mMol) oftricyclo-(2.2.1.0².6)-hept-3-yl-(4-pyridyl)-ketone in anhydrous toluenewas added while stirring and boiling to a suspension of 3.5 g. (89.7mMol) of sodium amide in 45 ml. of anhydrous toluene, followed byetherification for 2 hours as in Example 3 with 12.16 g. (89.7 mMol) ofβ-diethyl amino ethyl chloride in anhydrous toluene.

The crude base obtained by working up the reaction mixture in accordancewith Example 3 was suspended in water, followed by the dropwise additionwhile cooling with ice of a solution of 8.83 g. of concentratedhydrochloric acid in 20 ml. of ice water. After extraction with a totalof 100 ml. of ether, the aqueous phase is separated off and alkalizedwhile cooling with a solution of 8.95 ml. of 10N sodium hydroxide in 20ml. of water. The base precipitated was extracted with ether, the etherphase dried, concentrated and fractionated.

The hydrochloride was synthesized while cooling with ice by adding 2Nhydrochloric acid to a solution of the base in chloroform, brieflyextracting the organic phase by shaking with a little water, drying thechloroform solution with anhydrous sodium sulphate, concentrating thesolvent by evaporation and rubbing with ether.

Monohydrochloride: Mp.: 122°-125° C.

EXAMPLE 24N,N-Diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-2-thienyloxy]-ethyl}-amine

A mixture of 3.8 g. (79.1 mMol) of 50% sodium hydride dispersion(purified as in Example 6) in 80 ml. of dimethyl sulphoxide was heatedfor 1 hour at 70 - 80° C. until the evolution of hydrogen was over, asolution of 16 g. (78.2 mMol) oftricyclo-2.2.1.0².6)hept-3-yl-(2-thienyl)-ketone in 25 ml. of dimethylsulphoxide added dropwise while stirring under nitrogen at roomtemperature, the reaction mixture stirred for 1 hour at room temperatureand etherified in accordance with Example 5 with 10.7 g. (79.1 mMol) ofβ-diethyl amino ethyl chloride in 14 ml. of dimethyl sulphoxide for 1hour at 50°-60° C. and then for 15 hours at room temperature. Afterworking up as in Example 5, the crude base was purified to the stage ofits hydrochloride, purification of the base liberated was completed byseparation through an aluminium oxide column, followed finally bycharacterisation again in the form of the hydrochloride.

Hydrochloride: Mp.: 141°-144° C.

                  EXAMPLE 25                                                      ______________________________________                                        Coated tablets                                                                                    1 kernel contains:                                        ______________________________________                                        N,N-Diethyl-N-{2-[α-(tricyclo-                                           (2.2.1.0.sup.2.6)hept-3-ylidene)-                                             benzyloxy]-ethyl}-amine-hydro-                                                chloride (corresponds to 10 mg.                                               of the base compound)                                                                              11.223    mg.                                           polyvinylpyrrolidone (product                                                  Kollidon 25 of BASF) 0.225     mg.                                           corn starch           49.400    mg.                                           lactose               37.100    mg.                                           sec. calcium phosphate, anhydrous                                                                   35.200    mg.                                           gelatine              1.852     mg.                                           talcum                4.000     mg.                                           magnesium stearate    1.000     mg.                                                                 140.000   mg.                                           ______________________________________                                    

The corn starch, lactose and calcium phosphate are passed through a 1mm. sieve, are homogeneously mixed and are moistened with a 4% aqueoussolution of the gelatine. The resulting mixture is passed through a 2mm. sieve and dried until a relative humidity of 45% (measured by meansof a sample hygrometer). The resulting product and the active compound,talcum and magnesium stearate are passed through a 0.75 mm. sieve andthereafter are homogeneously mixed. The product which now is ready forpressing, is pressed to kernels having a diameter of 7 mm., a camberradius of 5 mm. and a weight of 140 mg. each. The kernels are checked ina control laboratory for mistakes. Thereafter, they are coated in ausual way with 5 mg. of a coating consisting of an acrylic methacrylicester copolymer, softening agents and colour pigments.

                  EXAMPLE 26                                                      ______________________________________                                        Suppositories                                                                                   1 suppository contains:                                     ______________________________________                                        N,N-Diethyl-N-{2-[α-(tricyclo-                                           (2.2.1.0.sup.2.6)hept-3-ylidene)-                                             benzyloxy]-ethyl}-amine-hydro-                                                chloride (corresponds to 20 mg.                                               of the base compound)                                                                            22.446      mg.                                           hardened fat DAB 7  1.977.554   mg.                                                               2.000.000   mg.                                           ______________________________________                                    

The active compound is sieved to a particle size of 75 micrometers. Itis slowly poured into the molten fat at 40° C. with thorough stirringand thus homogeneously mixed. The mixture is formed into suppositoriesweighing 2 g. each by means of molds or PVC film multiple molds.

                  EXAMPLE 27                                                      ______________________________________                                        Injection solutions                                                                                 2 cc. contain:                                          ______________________________________                                        N,N-Diethyl-N-{2-[α-tricyclo-                                            (2.2.1.0.sup.2.6)hept-3-ylidene)-                                             benzyloxy]-ethyl}-amine                                                                              10.000   mg.                                          sodium dihydrogen phosphate × 2 H.sub.2 O                                                       11.544   mg.                                          sodium monohydrogen phosphate × 12 H.sub.2 O                                                    45.120   mg.                                          ethanol                 0.200    cc.                                          emulgator (ethoxylated castor oil,                                             product Cremophor EL of BASF)                                                                        40.000   mg.                                          aqua pro injectione, upt to a total                                            volume of              2.000    cc.                                          ______________________________________                                    

The active compound is dissolved in a mixture of the ethanol and theemulgator and the resulting solution is poured into the solution of thephosphates in the water with stirring. The resulting solution isfiltered through a steril Seitz-EKS-filter under aseptic conditions andunder nitrogen and then is filled into ampoules of brown glas of 2.15cc. each under aseptic conditions and under nitrogen.

What we claim is:
 1. A compound selected from the group consisting ofthe basic enol ethers having the formula I ##STR10## wherein R₁represents a member selected from the group consisting of theunsubstituted phenyl group and the phenyl group substituted by membersselected from the group consisting of halogen, lower alkyl having from 1to 4 carbon atoms, nitro, trifluoromethyl, hydroxy and lower alkoxyhaving from 1 to 4 carbon atoms, alk is a member selected from the groupconsisting of the linear and branched alkylene groups having from 2 to 4carbon atoms, and R₂ and R₃, which may be the same or different,represent members selected from the group consisting of hydrogen andalkyl having 1 to 4 carbon atoms, and the pharmacologically acceptableacid addition salts.
 2. A compound as claimed in claim 1, wherein R₁represents a member selected from the group consisting of the phenylgroup and the phenyl group monosubstituted in the ortho position by amember selected from the group consisting of bromine, chlorine,fluorine, lower alkyl having from 1 to 4 carbon atoms, nitro,trifluoromethyl, hydroxy and lower alkoxy having from 1 to 4 carbonatoms, alk is the ethylene group and both R₂ and R₃ represent the ethylgroup.
 3. A compound selected from the group consisting ofN,N-diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-benzyloxy]-ethyl}-amineand its pharmacologically acceptable acid addition salts.
 4. A compoundselected from the group consisting ofN,N-diethyl-N-{2-[α-(tricyclo-(2.2.1.0².6)hept-3-ylidene)-o-methyl-benzyloxy]-ethyl}-amineand its pharmacologically acceptable acid addition salts.